CN112521392A - Purification method of chlorin e6 - Google Patents
Purification method of chlorin e6 Download PDFInfo
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- CN112521392A CN112521392A CN201910879722.1A CN201910879722A CN112521392A CN 112521392 A CN112521392 A CN 112521392A CN 201910879722 A CN201910879722 A CN 201910879722A CN 112521392 A CN112521392 A CN 112521392A
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- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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Abstract
The invention belongs to the field of medicines, and particularly relates to a purification method of chlorin e 6. The purification method comprises the steps of adding alkali to form salt and adding acid to dissociate, namely dissolving a crude chlorin e6 product in a salt forming solvent, adding alkali to form salt, crystallizing and filtering, then dissolving a filter cake in a dissociating solvent, adding acid to dissociate, and crystallizing to obtain high-purity chlorin e 6. The method has the advantages of simple and stable process operation and high purification efficiency.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a purification method of chlorin e 6.
Background
Photodynamic therapy is another new tumor treatment technology after surgery, radiotherapy and chemotherapy. The treatment is based on irradiating tumor tissues enriched with photosensitizer by light with a certain wavelength, and inducing effects such as photodynamic and the like by the photosensitizer, so that the tumor tissues are necrotized to show a treatment effect. Research shows that the chlorin e6 has reliable photodynamic curative effect on mouse solid sarcoma-180 transplantation tumor, and compared with the photosensitizer clinically used at home and abroad, the photosensitizer has the characteristics of definite chemical structure, higher absorption coefficient of a red light treatment area by one order of magnitude than that of a porphyrin preparation, strong photosensitization, high clearance speed in vivo, low toxicity and the like.
The synthesis method of chlorin e6 reported in the literature (for example, CN201810834227.4) is to prepare the chlorin by hydrolyzing methyl pheophorbide a as a raw material in a mixed solvent of an organic solvent and water under an alkaline condition. Chlorin e6 is sensitive to light, oxygen and temperature, so the salt of chlorin e6 is generally used clinically to improve its stability and water solubility.
The raw material chlorin e6 crude product used by the invention is also prepared by the method, and the purity of chlorin e6 prepared by the method is generally between 90% and 96%. The purity of chlorin e6 as a prodrug is still low, but few methods for efficiently purifying chlorin e6 are reported at present. WO2008054050A1 discloses a preparation method of a high-purity chlorin e6 sodium salt, which comprises the steps of extracting and refining chlorella to obtain chlorophyll a with high purity, and then preparing the chlorin e6 sodium salt with the purity of 95-99%. In the patent, the extraction and purification process of the chlorophyll a is complex, a high-speed centrifuge, extremely low temperature (-20 ℃) and other conditions are needed, and the purity of the sodium salt of the prepared chlorin e6 depends on the purity and the preparation process of the chlorophyll a. Therefore, the method has the defects of high equipment requirement, unsuitability for scale-up production, unstable process and the like.
Summary of The Invention
The invention provides a method for efficiently purifying chlorin e6, which can improve the purity of chlorin e6 with the purity of 90-96% to more than 99% through one-time refining. Chlorin e6 with purity less than 90% can be purified to more than 99% by multiple refining. The chemical structural formula of chlorin e6 is shown as follows:
briefly, the method of the present invention uses crude chlorin e6 as raw material, and obtains high purity chlorin e6 (preferably, purity of 99% or more, such as 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, or even 99.5% or more) through steps of salt formation with base and acid dissociation. Specifically, the method comprises the steps of dissolving a crude chlorin e6 product in a salt forming solvent, adding alkali at a certain temperature to form salt, cooling and crystallizing, and filtering; dissolving the filter cake in a dissociation solvent, adding acid to adjust the pH value to 3-4 at a certain temperature, dissociating and crystallizing, and drying to obtain the chlorin e6 with the purity of more than 99%.
In the refining process, the salt-forming solvent used is not limited as long as the solvent can dissolve chlorin e6, is beneficial to salt-forming crystallization of chlorin e6 and alkali, and can effectively improve the purity (including impurity removal) of chlorin e6 salt. The salifying solvent is selected from one or a mixture of several of the following solvents: ketone solvents such as acetone, butanone, methyl isopropyl ketone, and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran, 1, 4-dioxane, etc.; halogenated alkane solvents such as dichloromethane, dichloroethane, chloroform, etc.; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, etc.; nitrile solvents such as acetonitrile, propionitrile, and the like; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, etc.; an alkane solvent such as petroleum ether, n-hexane, n-heptane, etc.; aromatic hydrocarbon solvents such as benzene, toluene, xylene, etc.; preferred are tetrahydrofuran, acetone, ethyl acetate, acetonitrile, ethanol, toluene, dichloromethane or a mixed solvent thereof, and more preferred are tetrahydrofuran, acetone, dichloromethane or a mixed solvent thereof. In order to obtain chlorin e6 with higher yield and higher purity, the amount (volume) of the salt-forming solvent is 1-60 times, preferably 3-20 times of that of chlorin e6 (mass). The temperature for adding alkali to form salt is 0-100 deg.C, preferably 30-60 deg.C.
In the above refining process, suitable base may be inorganic base such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, etc., organic base such as diethylamine, meglumine, ethanolamine, N-methylmorpholine, etc., preferably organic base, more preferably meglumine or ethanolamine. The amount of the base used is 0.5 to 10 times (molar ratio) that of chlorin e6, preferably 1 to 2 times (molar ratio). Suitable acids are selected from inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, organic acids such as formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like, preferably inorganic acids, more preferably hydrochloric acid. The amount of the acid to be used depends on the pH of the reaction solution after the addition, and the pH is controlled within a range of 1 to 6, preferably 3 to 4.
In the refining process, the dissociation solvent is selected from one or more of the following solvents: aqueous solvents such as water, aqueous inorganic salts, and the like; alcohol solvents such as methanol, ethanol, isopropanol, and the like; ketone solvents such as acetone, butanone, methyl isopropyl ketone, and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran, 1, 4-dioxane, etc.; nitrile solvents such as acetonitrile, propionitrile, and the like. The amount (volume) of the dissociation solvent is 0.1 to 60 times, preferably 0.5 to 10 times of that of the dihydroporphine e6 salt (by mass). The e6 salt is preferably dissolved in water and is easy to detect the pH value, so the dissociation solvent is preferably an aqueous solvent or an aqueous mixed solvent. The temperature for acid addition and dissociation is-20 to 100 ℃, and preferably 0 to 10 ℃.
The refining process takes a crude chlorin e6 product as a raw material, and the high-purity chlorin e6 is prepared by sequentially carrying out alkali salt formation and acid dissociation processes. The specific operation is as follows:
(1) adding alkali to form salt
Dissolving the crude chlorin e6 product in the salifying solvent, adding one of the bases for salifying at 30-60 ℃, keeping the temperature at 30-60 ℃, stirring, cooling in an ice water bath for crystallization, and filtering, wherein a filter cake is used for the dissociation process;
(2) adding acid for dissociation
Adding the filter cake obtained in the step (1) into a dissociation solvent, adding acid to adjust the pH value to 3-4 at 0-10 ℃, stirring for crystallization, and filtering to obtain the chlorin e6 with the purity of more than 99%.
In the refining process, the steps of adding alkali for salt formation and adding acid for dissociation are carried out under the protection of light and inert gas, wherein the inert gas is preferably argon and nitrogen.
The present invention provides high purity chlorin e6 prepared by the purification method of the present invention.
The invention also provides application of the high-purity chlorin e6 serving as a photosensitizer for treating tumors or application of the high-purity chlorin e6 in preparing the photosensitizer for treating the tumors.
Aiming at the problems that the purity of chlorin e6 is low and no efficient purification method exists at present, the inventor develops a method for purifying chlorin e6, which is suitable for scale-up production. During the development process, we surprisingly found that under the conditions of shielding from light, inert gas and certain temperature, the chlorin e6 is salified in a proper solvent, and impurities in the chlorin e6 are effectively removed. And then dissociating the salt in a proper solvent at a certain temperature to obtain the high-purity chlorin e 6.
The invention utilizes the characteristic that the solubility of chlorin e6 is enhanced after the chlorin e6 and alkali (such as meglumine) are salified, the salified composite compound is dissolved in an organic solvent for purification, and then the chlorin e6 is separated by adding acid. The method has the advantages of simple and stable process operation and high purification efficiency.
Brief Description of Drawings
FIG. 1 shows the result of purity test of crude chlorin e 6;
FIG. 2 is the result of purity measurement of chlorin e6 after salification with meglumine;
FIG. 3 shows the result of purity measurement of chlorin e6 after dissociation of meglumine salt;
FIG. 4 shows the result of purity measurement of chlorin e6 after salification with ethanolamine; and
FIG. 5 shows the result of purity measurement of chlorin e6 ethanolamine salt after dissociation.
The specific implementation mode is as follows:
the technical solution of the present invention will be clearly and completely described below with reference to the specific embodiments of the present invention. It is to be understood that the described embodiments are part, and not all, of the present invention. All variations that can be made by a person skilled in the art on the basis of the embodiments of the invention without inventive step fall within the scope of the invention as claimed.
The reagents and starting materials used in the present invention are commercially available. The purity of the crude chlorin e6 product is 91.85%, and the pattern is shown in figure 1.
Example 1: salt formation of chlorin e6 with meglumine
Under the protection of argon, 200g of crude chlorin e6 is added into 1L of tetrahydrofuran, heated to 50-60 ℃, and stirred to be dissolved. 196.31g of meglumine is added, stirred for 1 hour, and then cooled to 0-10 ℃ for crystallization for 2 hours. Filtration, cake leaching with 200mL THF, drying, 357.07g chlorin e6 meglumine salt, yield 90.10%.
Example 2: dissociation of chlorin e6 meglumine salt
Under the protection of argon, 350g of chlorin e6 meglumine salt in example 1 is dissolved in 1L of mixed solution of tetrahydrofuran and water, the temperature is reduced to 0-10 ℃, 10% hydrochloric acid solution is dropwise added to adjust the pH value to be 3-4, more solid is separated out, stirring is continuously carried out for crystallization for 2h, filtration is carried out, a filter cake is washed by 350ml of water, and vacuum drying is carried out, so that 168.15g of chlorin e6 is obtained, and the yield is 95.20%.
Example 3: salt formation of chlorin e6 with ethanolamine
Under the protection of argon, 100g of crude chlorin e6 is added into 1.20L of acetone, heated to 50-60 ℃, and stirred to be dissolved. Adding 30.71g of ethanolamine, stirring for 2h, cooling to 0-10 ℃, cooling and crystallizing for 2 h. Filtration, cake rinsing with 50mL acetone, and drying gave 117.26g of chlorin e6 ethanolamine salt in 89.71% yield.
Example 4: dissociation of chlorin e6 ethanolamine salt
Under the protection of argon, 115g of chlorin e6 ethanolamine salt in example 3 is dissolved in 690mL of mixed solution of tetrahydrofuran and water, the temperature is reduced to 0-10 ℃, 10% hydrochloric acid solution is dropwise added to adjust the pH value to be 3-4, more solid is precipitated, stirring is continuously carried out for crystallization for 2h, filtration is carried out, a filter cake is washed by 100mL of water, and vacuum drying is carried out, so that 83.49g of chlorin e6 is obtained, and the yield is 94.90%.
The above examples 1-4 are the results of the experiment of salifying and dissociating the crude chlorin e6 with different bases in different solvents, and are summarized in the following tables 1-2 and fig. 2-5. According to experimental results, the method can prepare the product with the purity of more than 99% on the premise of high yield.
Table 1: refining effect of dihydroporphin e6 and meglumine salt
| Purity of | Yield of | |
| Crude dihydroporphin e6 product | 91.85％ | -- |
| Chlorin e6 meglumine salt | 99.39％ | 90.10％ |
| Refined dihydroporphin e6 product | 99.23％ | 95.20％ |
Table 2: refining effect of dihydroporphin e6 and ethanolamine salt formation
| Purity of | Yield of | |
| Crude dihydroporphin e6 product | 91.85％ | -- |
| Chlorin e6 ethanolamine salt | 99.23％ | 89.71％ |
| Refined dihydroporphin e6 product | 99.02％ | 94.90％ |
The method for purifying the chlorin e6 fills the gap that no high-purity chlorin e6 preparation process exists at present. The method is verified by a large amount of experimental data, has stable refining process and is suitable for preparing high-purity chlorin e6 in an amplification mode. Meanwhile, the solvent used in the method can be recycled, so that the treatment process of the waste solvent and the environmental pollution are reduced, and the production cost is saved.
Claims (14)
1. A purification method of chlorin e6 comprises the steps of taking a crude chlorin e6 product as a raw material, adding alkali to form salt and adding acid to dissociate to obtain high-purity chlorin e 6.
2. The method for purifying chlorin e6 of claim 1, wherein the steps of salifying with base and dissociating with acid comprise:
1) dissolving the crude chlorin e6 in a salt forming solvent, adding alkali to form salt, crystallizing and filtering; and
2) dissolving the filter cake in a dissociation solvent, adding acid for dissociation, and crystallizing to obtain the high-purity chlorin e 6.
3. The method for purifying chlorin e6 as claimed in claim 2, wherein the salt-forming solvent is selected from one or more of the following solvents: ketone solvents such as acetone, butanone, methyl isopropyl ketone; ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane; halogenated alkane solvents such as dichloromethane, dichloroethane, chloroform; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate; nitrile solvents such as acetonitrile, propionitrile; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol; alkane solvents such as petroleum ether, n-hexane, n-heptane; aromatic hydrocarbon solvents such as benzene, toluene, xylene; preferred are tetrahydrofuran, acetone, ethyl acetate, acetonitrile, ethanol, toluene, dichloromethane or a mixed solvent thereof, and more preferred are tetrahydrofuran, acetone, dichloromethane or a mixed solvent thereof.
4. The method for purifying chlorin e6 as claimed in claim 2 or 3, wherein the salt-forming solvent is used in an amount of 1-60 times (v/mass), preferably 3-20 times (v/mass) that of chlorin e 6.
5. A method of purifying chlorin e6 as claimed in any one of claims 1 to 4 wherein the temperature of the addition of base to form the salt is in the range of 0 to 100 ℃, preferably 30 to 60 ℃.
6. The method for purifying chlorin e6 as claimed in any one of claims 1-5, wherein the suitable base is selected from inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, organic bases such as diethylamine, meglumine, ethanolamine and N-methylmorpholine, preferably organic bases, more preferably meglumine or ethanolamine; suitable acids are selected from the group consisting of mineral acids, such as hydrochloric acid, sulfuric acid and phosphoric acid, organic acids, such as formic acid, acetic acid, methanesulfonic acid and p-toluenesulfonic acid, preferably mineral acids, more preferably hydrochloric acid.
7. The method for purifying chlorin e6 as claimed in any one of claims 1-6, wherein the amount of base is 0.5-10 times (molar ratio), preferably 1-2 times (molar ratio) the amount of chlorin e6, and the amount of acid is such that the pH of the reaction solution after addition is 1-6, preferably 3-4.
8. The method for purifying chlorin e6 as recited in any one of claims 2 to 7, wherein the dissociating solvent is selected from one or more of the following solvents: aqueous solvents such as water, aqueous inorganic salts; alcohol solvents such as methanol, ethanol, isopropanol; ketone solvents such as acetone, butanone, methyl isopropyl ketone; ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane; nitrile solvents such as acetonitrile, propionitrile; an aqueous solvent or a mixed solvent containing water is preferable.
9. The method for purifying chlorin e6 as claimed in any one of claims 2-8, wherein the amount of dissociating solvent is 0.1-60 times (v/mass), preferably 0.5-10 times (v/mass) of the amount of chlorin e 6.
10. A method of purifying chlorin e6 as claimed in any one of claims 1-9, wherein the temperature of the acid addition dissociation is-20 to 100 ℃, preferably 0 to 10 ℃.
11. The method for purifying chlorin e6 as claimed in any one of claims 1 to 10, wherein the purity of high purity chlorin e6 is 99% or more.
12. The method for purifying chlorin e6 as recited in any one of claims 1-11, wherein the steps of salification with base and dissociation with acid are performed under protection of light and inert gas, preferably argon and nitrogen.
13. A high purity chlorin e6, prepared by the purification method of any one of claims 1-12.
14. Use of the high purity chlorin e6 of claim 13 in the preparation of a photosensitizer for the treatment of tumors.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116162092A (en) * | 2023-03-03 | 2023-05-26 | 康俄(上海)医疗科技有限公司 | Preparation method of chlorin e6 triglucamine salt |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116162092A (en) * | 2023-03-03 | 2023-05-26 | 康俄(上海)医疗科技有限公司 | Preparation method of chlorin e6 triglucamine salt |
| CN116162092B (en) * | 2023-03-03 | 2023-10-10 | 康俄(上海)医疗科技有限公司 | Preparation method of chlorin e6 triglucamine salt |
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